HIV Infection
Conditions
Keywords
HIV, Efavirenz, Central Nervous System (CNS), Lumbar puncture, Dose reduction
Brief summary
Persistent HIV infection in the central nervous system (CNS) compartment may put subjects at risk of developing HIV-related brain disease. Important factors associated with the development of HIV-related brain disease include therapeutic concentrations of antiretroviral drugs in the CNS. Conflicting evidence regarding the CNS exposure of the antiretroviral drug used for the encore1 study, efavirenz (EFV) have been described in related studies. There were recent study of two small series assessment of EFV exposure in the cerebral spinal fluid (CSF); one group reported small detectable EFV concentrations, while another observed undetectable EFV exposure in the CSF. Also, in a larger reported series comprising of 80 subjects on EFV-containing antiretroviral therapy, a CSF to plasma concentration suggested that there is limited movement of EFV out of the CSF. In HIV-1 infected subjects at steady state, EFV plasma level parameters are dose proportional following 200mg, 400mg, and 600mg daily doses. The CNS exposure of EFV at different daily dosing has not been described.
Interventions
DRUGEfavirenz
600mg qd; 3 x 200mg qd
Sponsors
Imperial College London
Kirby Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* All subjects entering into the main study protocol at participating centres will be eligible to enter this sub-study.
Exclusion criteria
* Existing neurological disease which in the opinion of the investigator would be a contra-indication to lumbar puncture examination * CNS opportunistic infections in the past 12 weeks of randomisation * Bacterial or viral meningitis in the past 12 weeks of randomisation * Head injury requiring medical assessment in the past 12 weeks of randomisation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| comparison of mean CSF concentration of EFV from both doses after week 24. | 24 weeks | measure the CSF exposure of EFV when dosed at 400mg and 600mg daily. Efavirenz plasma and CSF concentrations will be analysed and CSF:plasma ratios will be compared. Associations between plasma and CSF concentrations and relationship to study clinical parameters will be assessed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments | 24 weeks | — |
| The relationship between CSF EFV exposure and other study parameters such as race and sex. | 24 weeks | — |
| The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL) | 24 weeks | — |
| CSF EFV exposure and plasma exposure (CSF:plasma ratio) using statistical analysis | 24 weeks | The relationship between CSF EFV exposure and plasma exposure (CSF:plasma ratio), both for protein bound and free plasma EFV exposure. |
| Relationship between plasma HIV RNA and CSF HIV RNA | 24 weeks | — |
| CSF biomarker analysis after 12 - 24 weeks of study therapy | 24 weeks | — |
| comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration | 24 weeks | — |
| CSF HIV RNA measurement after 12 - 24 weeks of study therapy | 24 weeks | — |
Countries
Germany, Thailand, United Kingdom
Outcome results
None listed